Biomedical subjects

Edward Kim

Publications and source records attributed to Edward Kim.

At least 19 recordsLinked to original sources

PubMed2006

Transient receptor potential vanilloid 1, calcitonin gene-related peptide, and substance P mediate nociception in acute pancreatitis.

The mechanism of pancreatitis-induced pain is unknown. In other tissues, inflammation activates transient receptor potential vanilloid 1 (TRPV1) on sensory nerves to liberate CGRP and substance P (SP) in peripheral tissues and the dorsal horn to cause neurogenic inflammation and pain, respectively. We evaluated the contribution of TRPV1, CGRP, and SP to pancreatic pain in rats. TRPV1, CGRP, and SP were coexpressed in nerve fibers of the pancreas. Injection of the TRPV1 agonist capsaicin into the pancreatic duct induced endocytosis of the neurokinin 1 receptor in spinal neurons in the dorsal horn (T10), indicative of SP release upon stimulation of pancreatic sensory nerves. Induction of necrotizing pancreatitis by treatment with L-arginine caused a 12-fold increase in the number of spinal neurons expressing the proto-oncogene c-fos in laminae I and II of L1, suggesting activation of nociceptive pathways. L-arginine also caused a threefold increase in spontaneous abdominal contractions detected by electromyography, suggestive of referred pain. Systemic administration of the TRPV1 antagonist capsazepine inhibited c-fos expression by 2.5-fold and abdominal contractions by 4-fold. Intrathecal, but not systemic, administration of antagonists of CGRP (CGRP(8-37)) and SP (SR140333) receptors attenuated c-fos expression in spinal neurons by twofold. Thus necrotizing pancreatitis activates TRPV1 on pancreatic sensory nerves to release SP and CGRP in the dorsal horn, resulting in nociception. Antagonism of TRPV1, SP, and CGRP receptors may suppress pancreatitis pain.

Animals↗

PubMed2006

Complications associated with the posterolateral approach for pilon fractures.

OBJECTIVE: To review the complication rates of open reduction and internal fixation (ORIF) of tibial pilon fractures using the posterolateral approach. DESIGN: Retrospective review. SETTING: Two level I trauma centers. PATIENTS: Nineteen consecutive pilon fractures at an average of 13 (range, 13-45) months follow-up. Average age 46 (range, 21-72) years. Four of 19 were open fractures. INTERVENTION: Because of the high incidence of wound complications associated with the anterior approach for pilon fractures, patients were treated with initial temporary external fixation followed by delayed ORIF through the posterolateral approach to the distal tibia. The hypothesis was that the abundant soft-tissue coverage of the posterior distal tibia would decrease the rate of wound complications. MAIN OUTCOME MEASUREMENTS: The incidence of wound complications, nonunion, and early posttraumatic arthritis. This was a chart and radiograph retrospective review. RESULTS: The mean time to definitive treatment was 13 (range 2-30) days. Nine of 19 patients (47%) developed complications. There were 6 patients with wound problems, 2 patients with aseptic nonunions, 2 patients with infected nonunions, 3 tibiotalar fusions, and 1 patient with a 3-mm step off. In total, there were 14 major complications in 9 patients. Ten of 19 patients did not have any complication. CONCLUSIONS: The posterolateral approach does not eliminate the complications common to other approaches, but does offer a potential alternative when soft tissue concerns prevent other approaches. We do not recommend the posterolateral approach for the routine treatment of tibial pilon fractures.

Adult↗

PubMed2006

The value of the dedicated orthopaedic trauma operating room.

BACKGROUND: Trauma centers and orthopaedic surgeons have traditionally been faced with limited operating room (OR) availability for fracture surgery. Orthopaedic trauma cases are often waitlisted and done late at night. We investigated the feasibility of having an unbooked orthopaedic trauma OR to reduce nighttime cases and improve OR flow. METHODS: A retrospective analysis was performed for two 1 year time periods before and after the introduction of an unbooked trauma OR. The unbooked trauma OR is kept open for urgent and semi-urgent cases from 7:45 am to 5 pm 6 days per week, and is under the control of Orthopaedics; no elective cases are scheduled in the unbooked trauma room. We collected OR time data on two common surgical cases (dynamic hip screw and closed femoral nailing) done before and after introduction of the unbooked orthopaedic trauma OR. We also reviewed data on waitlist cases, surgical time, anesthetic times, OR utilization, and surgical complications before and after the introduction of the unbooked trauma room. RESULTS: The availability of the unbooked trauma OR significantly improved operating suite flow. The proportion of hip fractures done after 5 pm was reduced by 72% (p<0.01). The number of all orthopaedic waitlist cases started after 5 pm was reduced by 6% (p<0.021). The distinct shift toward performing add-on cases during daytime hours resulted in a 6% reduction in OR over-utilization. Closed femoral nailing done at night required significantly more OR time (261 minutes versus 219 minutes, p<0.04). Hip fracture surgeries and femoral nailings done at night were noted to have a higher incidence of surgical complications (p<0.04 and p<0.036). CONCLUSION: The availability of an unbooked orthopaedic trauma room resulted in a measurable shift from performing "add-on" cases to daytime surgery and may reduce complications. We recommend that hospitals and orthopaedic trauma services commit resources toward having an open OR reserved for orthopaedic trauma.

Appointments and Schedules↗

PubMed2006

Obesity, dyslipidemias and erectile dysfunction: a report of a subcommittee of the sexual medicine society of North America.

Because of increasingly sedentary lifestyles and diets higher in saturated fats, obesity and dyslipidemias are common and increasing in prevalence in Westernized countries. Longitudinal population-based studies clearly demonstrate that dyslipidemias and obesity, as well as factors such as hypertension, diabetes, and smoking, are major risk factors for atherosclerosis. Both clinical and animal models of endothelial dysfunction confirm that atherosclerosis leads to increased cerebrovascular and cardiovascular morbidity. Clinical studies with hypolipidemic agents demonstrate that hydroxy-3-methylglutaryl coenzyme A reductase inhibitors can decrease the risk of vascular morbidity. An increasing body of evidence from animal models demonstrates that hypercholesterolemia and atherosclerosis are risk factors for the development of erectile dysfunction (ED). This causal relationship between obesity and dyslipidemias with the development of ED in humans still needs further definition with convincing peer-reviewed scientific studies. The challenge for the future will be to define the benefit of controlling obesity and dyslipidemias on the development of ED and improvement of erectile function.

Animals↗

PubMed2006

A pilot study of quetiapine treatment of aggression due to traumatic brain injury.

In a 6-week open-label, flexible dose pilot study of quetiapine for treatment of aggression secondary to traumatic brain injury (TBI), seven subjects who were at least 3-months post-injury were enrolled. The Overt Aggression Scale - Modified (OAS-M) and Clinical Global Impression (CGI) were primary outcome measures. Administration of quetiapine at doses of 25 to 300 mg daily was efficacious and well-tolerated in reducing irritability and aggression resulting from TBI, with an associated improvement in cognitive functioning.

Aggression↗

PubMed2006

Efficacy of the team solutions program for educating patients about illness management and treatment.

OBJECTIVE: Despite the demonstrated efficacy of psychosocial approaches to schizophrenia treatment that include a psychoeducational component, such as illness management, the implementation of these approaches into routine mental health treatment has been slow. The authors sought to examine the efficacy of a comprehensive, modularized, psychoeducational program called Team Solutions, which was designed to educate patients with major mental illnesses about their illness and how to manage it. Team Solutions was chosen for study because it is available over the Internet and other venues at no cost and is used by mental health agencies across the United States and Canada. METHODS: Seventy-one persons with schizophrenia or schizoaffective disorder from three day treatment settings participated in this randomized, single-blind study. Participants were randomly assigned to attend one of two interventions: the Team Solutions intervention, which consisted of participating in a 24-week psychoeducational group focused on illness management, or treatment as usual. RESULTS: For participants who attended the experimental group, significant improvement was observed in knowledge about schizophrenia. In addition, client satisfaction was high. However, no changes were observed in symptoms or functioning. CONCLUSIONS: Results indicated that participation in the Team Solutions psychoeducational group improved participants' knowledge. However, participation in the program did not demonstrate superiority over treatment as usual with respect to secondary and tertiary outcomes, such as symptom severity, treatment adherence, and global functioning.

Adult↗

PubMed2005

Hypoxia-inducible factor 1alpha and antiangiogenic activity of farnesyltransferase inhibitor SCH66336 in human aerodigestive tract cancer.

BACKGROUND: The farnesyltransferase inhibitor SCH66336, in combination with other receptor tyrosine kinase inhibitors, inhibits the growth of non-small-cell lung cancer (NSCLC) cells. We examined whether SCH66336 inhibits angiogenesis of aerodigestive tract cancer cells. METHODS: Antiangiogenic activities of SCH66336 against NSCLC, head and neck squamous cell carcinoma (HNSCC), and endothelial cells were examined with cell proliferation, capillary tube formation, and chick aorta (under hypoxic, normoxic, insulin-like growth factor I (IGF)-stimulated, and unstimulated conditions); reverse transcription-polymerase chain reaction; and western blot analyses. The specific roles of the ubiquitin-mediated proteasome machinery, mitogen-activated protein kinase (MAPK) and Akt pathways, and heat shock protein 90 (Hsp90) in the SCH66336-mediated degradation of hypoxia-inducible factor 1alpha (HIF-1alpha) were assessed with ubiquitin inhibitors and adenoviral vectors that express constitutively active MAP kinase kinase (MEK)1, constitutively active Akt, or Hsp90. RESULTS: SCH66336 showed antiangiogenic activities and decreased the expression of vascular endothelial cell growth factor (VEGF) and HIF-1alpha in hypoxic, IGF-stimulated, and unstimulated aerodigestive tract cancer and endothelial cells. SCH66336 reduced the half-life of the HIF-1alpha protein, and ubiquitin inhibitors protected the hypoxia- or IGF-stimulated HIF-1alpha protein from SCH66336-mediated degradation. SCH66336 inhibited the interaction between HIF-1alpha and Hsp90. The overexpression of Hsp90, but not constitutive Akt or constitutive MEK, restored HIF-1alpha expression in IGF-stimulated or hypoxic cells but not in unstimulated cells. CONCLUSIONS: SCH66336 appears to inhibit angiogenic activities of NSCLC and HNSCC cells by decreasing hypoxia- or IGF-stimulated HIF-1alpha expression and to inhibit VEGF production by inhibiting the interaction between HIF-1alpha and Hsp90, resulting in the proteasomal degradation of HIF-1alpha.

Alkyl and Aryl Transferases↗

PubMed2005

Phase I study of the farnesyltransferase inhibitor BMS-214662 given weekly in patients with solid tumors.

PURPOSE: A phase I trial of BMS-214662, a selective farnesyltransferase inhibitor with significant preclinical antitumor activity in which drug was given as a weekly 1-hour infusion for four of six weeks, was conducted to evaluate the tolerability, pharmacokinetics, and pharmacodynamic effect on farnesyltransferase activity in peripheral blood mononuclear cells. EXPERIMENTAL DESIGN: BMS-214662 was given to 27 patients with solid tumors at 10 escalating dose levels (28-220 mg/m(2)) allowing intrapatient dose escalation; pharmacokinetics and pharmacodynamics were done at the first seven dose levels. RESULTS: Grade 4 neutropenia (four patients) was the most common dose-limiting toxicity followed by aminotransferase elevation (grade 3 alanine aminotransferase and grade 4 aspartate aminotransferase) and grade 3 dehydration. Most frequent toxicities were neutropenia in 11 (14%), anemia in 15 (19%), fatigue in 9 (12%), and nausea and diarrhea in 6 (8%) of courses, respectively. One minor response lasting 18 weeks in a patient with non-small cell lung cancer, serum calcitonin level reduction accompanied by disease stabilization in two of four patients with medullary thyroid carcinoma, and stable disease in 16 of 25 evaluable patients was seen. No correlation was observed between dose and C(max), total body clearance (mean, 26.15 +/- 10.88 L per hour per m(2)), volume of distribution at steady state (mean, 39.51 +/- 17.91 L/m(2)), or half-life (mean, 2.63 +/- 1.81 hours); a moderate correlation existed between dose given and systemic drug exposure (AUC). Substantial inhibition of peripheral blood mononuclear cell farnesyltransferase activity but near complete recovery by 24 hours was seen. CONCLUSION: BMS-214667 was well tolerated as a weekly 1-hour i.v. infusion for four of six weeks with evidence of pharmacodynamic effect. The study was terminated before maximum tolerated dose was reached. Alternative schedules of drug administration might result in improved pharmacodynamic profile.

Adolescent↗

PubMed2005

Management of rash and other toxicities in patients treated with epidermal growth factor receptor-targeted agents.

Inhibition of the epidermal growth factor receptor (EGFR) represents one of the most important avenues for research and development in the field of cancer therapy. The EGFR is a member of the ErbB receptor tyrosine kinase (TK) family, which also includes ErbB-2 (HER2/neu), ErbB-3 (HER3), and ErbB-4 (HER4). Current EGFR therapies available for use include monoclonal antibodies, such as cetuximab, and small-molecule EGFR TK inhibition by agents such as erlotinib. Side effects of these agents include dermatologic manifestations without the bone marrow suppressive properties of chemotherapy. Understanding of rash and how it relates to EGFR inhibitor toxicity and, perhaps more importantly, EGFR inhibitor response must be more clearly defined with clinical trials. The optimum management of rash in patients receiving anti-EGFR therapy remains somewhat controversial; this is secondary to imprecise classification of rash as well as the lack of clinical trials to determine the most appropriate treatment algorithm for these patients. We propose a treatment strategy to help aggressively treat dermatologic side effects allowing patients to continue receiving therapy without dose interruption or drug discontinuation.

Administration, Topical↗

PubMed2005

Optimizing chemotherapy and targeted agent combinations in NSCLC.

Chemotherapy extends life and provides symptom palliation for patients with advanced non-small cell lung cancer (NSCLC). Numerous trials have been conducted that evaluate a variety of doublet regimens, but the majority of trials have found equal efficacy among the treatment arms. Indeed, a plateau appears to have been reached with respect to survival associated with traditional cytotoxic drug regimens. It was initially hoped that the addition of novel targeted agents to conventional chemotherapy would produce significant survival benefits for patients with advanced NSCLC; however, most trials have failed to show such a benefit. There is no survival benefit associated with adding erlotinib or gefitinib to a chemotherapy regimen, although there is a significant improvement in survival associated with erlotinib monotherapy in the second- and third-line advanced disease setting. In contrast, the results of E4599 clearly demonstrate that the addition of bevacizumab to paclitaxel-carboplatin chemotherapy extends survival in a select group of patients with non-squamous cell NSCLC. E4599 also represents a rational approach to drug development that could be modeled in other trials, namely, the use of a large, well designed, randomized trial prior to beginning a traditional phase II approach. This strategy can lead to the identification of subgroups most likely to benefit, as well as those that might experience increased toxicity, such as patients with squamous cell carcinoma treated with bevacizumab. Another approach to optimizing targeted therapy involves selecting a chemotherapy regimen with the greatest potential for synergy based on preclinical modeling. Because docetaxel has been shown to prolong survival in second-line treatment, a number of novel agents have been combined with docetaxel in order to improve efficacy. Alternatively, investigators have sought to combine novel agents with either carboplatin-paclitaxel or cisplatin-gemcitabine in first-line treatment. A number of trials are underway that combine these agents with inhibitors of the epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and the proteasome, as well as COX2 inhibitors, and novel immunomodulators.

Journal Article↗

PubMed2005

Optimizing chemotherapy and targeted agent combinations in NSCLC.

Antibodies, Monoclonal↗

PubMed2004

Role of ProstaScint for brachytherapy in localized prostate adenocarcinoma.

ProstaScint (CYT-356 or capromab pendetide, Cytogen) is an 111In-labeled monoclonal mouse antibody specific for prostate-specific membrane antigen, a prostate transmembrane glycoprotein that is upregulated in prostate adenocarcinoma. ProstaScint scans are US Food and Drug Administration approved for pretreatment evaluation of metastatic disease in high-risk patients. They are also approved for post-prostatectomy assessment of recurrent disease in patients with a rising prostate-specific antigen level. This review explores the literature on ProstaScint and its use in guiding the treatment of prostate cancer. A novel technique for identifying areas of cancer within the prostate using ProstaScint images fused with pelvic computed tomography scans is also described. The identification of areas of high antibody signal provides targets for radiotherapeutic dose escalation, with the overall goals of improving treatment outcome while preserving adjacent tissue structures and decreasing treatment morbidity.

Adenocarcinoma↗

PubMed2003

Four-year biochemical outcome after radioimmunoguided transperineal brachytherapy for patients with prostate adenocarcinoma.

PURPOSE: To evaluate 4-year biochemical outcomes for patients with prostate adenocarcinoma who underwent radioimmunoguided (Prostascint) permanent prostate brachytherapy. METHODS AND MATERIALS: Eighty patients with clinical T1C-T3A NxM0 prostate cancer underwent ProstaScint-guided prostate brachytherapy using either (103)Pd or (125)I between February 1997 and December 2000. Sixty-seven patients underwent prostate brachytherapy alone, whereas 13 patients received neoadjuvant hormonal manipulation before implantation. Risk factors (RF) included PSA >10, Stage >or=T2b, and Gleason grade >or=7. Sixty patients had low-risk disease (0 RF), 17 were intermediate risk (1 RF), and 3 were high risk (2 RF). Biochemical disease-free survival (bDFS) was calculated using the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus criteria, a PSA cutoff of 1.0 ng/mL, and a PSA cutoff of 0.5 ng/mL. RESULTS: Four-year bDFS for the entire cohort was 97.4% using the ASTRO consensus criteria. Low-risk patients (60) had a 4-year bDFS of 100%; intermediate- and high-risk patients (20 patients) were 89.2%. The hormonally naïve group (67 patients) had a 4-year bDFS of 96.9% and a median PSA nadir of 0.2 ng/mL. Median time to nadir was 19.8 months (range: 1.9-53.2 months). For the neoadjuvant hormonal therapy group (13 patients), ASTRO-defined bDFS was 100%. Overall, 85.2% of patients had a posttreatment PSA <or=1.0 ng/mL, and 75.9% had a PSA <or=0.5 ng/mL at a median follow-up of 36 months. CONCLUSIONS: At a median follow-up of 36 months, ProstaScint-guided transperineal brachytherapy results in a high probability of actuarial 4-year biochemical disease-free survival for patients with localized prostate cancer.

Adenocarcinoma↗

PubMed2003

Brachytherapy: update and results.

Prostate cancer is the most common noncutaneous malignancy and the second most common cause of cancer mortality in American men. Treatment options for these patients include radical prostatectomy, external beam radiation therapy, hormonal therapy, and prostate brachytherapy. Patients with clinically and radiographically localized disease, especially young patients with few comorbid illnesses, are good candidates for prostate brachytherapy. Prostate brachytherapy has gained widespread acceptance throughout the past two decades and data from several large series of patients are now available. This article describes current techniques, treatment issues, and clinical results of permanent seed implants.

Brachytherapy↗

PubMed2003

Combination conformal radiotherapy and radioimmunoguided transperineal 103Pd implantation for patients with intermediate and unfavorable risk prostate adenocarcinoma.

PURPOSE: To report outcomes for prostate cancer patients treated with external beam radiation therapy (EBRT) and permanent prostate brachytherapy utilizing radioimmunoguided targeting of biological tumor volumes (BTVs). METHODS AND MATERIALS: Between February 1997 and October 2001, 66 patients with intermediate- to high-risk prostate cancer underwent EBRT and ProstaScint-guided transperineal brachytherapy. Thirty patients received neoadjuvant hormonal manipulation, while 36 patients did not. Median patient age was 66 years (range, 49-78 years). The median follow-up was 41 months (range, 24-78 months). No patients were lost to follow-up. Risk factors (RF) used for risk stratification included PSA >10 ng/ml (35 patients), Stage T2b or greater (22 patients), and Gleason score > or = 7 (55 patients). Results for biochemical disease free survival (bDFS) were reported using the ASTRO consensus definition for biochemical failure, PSA < or = 1.0 ng/mL or PSA< or = 0.5 ng/mL. Survival was estimated by the Kaplan-Meier method. RESULTS: Five-year overall survival was 93.1% and 5-year bDFS by the ASTRO definition was 89.3% with a median follow up of 41 months. Patients with intermediate- (1 RF) and high-risk (2-3 RF) prostate cancer exhibited 5-year ASTRO-defined bDFS of 100% and 81.9%, respectively. There was no significant difference in bDFS between the patients treated with or without hormone therapy (HT). The 5-year ASTRO-defined bDFS was 89.8% for the 30 patients treated with HT and 88.9% for the 36 patients who did not receive HT (p = 0.843). For the patients without HT the median PSA nadir was 0.11 ng/mL. The median time to nadir was 23 months (range, 6-66 months). CONCLUSIONS: With limited follow-up, the results of EBRT plus radioimmunoguided brachytherapy for intermediate- to high-risk prostate cancer appear favorable. The addition of HT did not appear to affect bDFS significantly, but interpretation is confounded by possible selection bias and the limited power of this study.

Adenocarcinoma↗

PubMed2003

Intraoperative radiotherapy in the multimodality approach to bone and soft tissue cancers.

IORT is a powerful tool for the management of cancer and has been shown to improve local control in the treatment of sarcomas in one prospective, randomized, controlled trial. IORT allows dose escalation in areas where escalation with EBRT would cause potentially excessive acute or late normal tissue toxicity. It has a unique toxicity profile but remains safe and effective when used in appropriately selected patients. In addition, IORT is becoming more widely available at different cancer centers and offers great flexibility in treatment planning for a wide variety of malignancies. As IORT use becomes more common, special care will be required to ensure that it is used by a multidisciplinary team of radiation oncologists and surgeons to ensure the best results for patients.

Adult↗

PubMed2002

The use of newer anticonvulsants in neuropsychiatric disorders.

Anticonvulsants are becoming increasingly popular for the management of psychiatric and neuropsychiatric syndromes. This may be related to antikindling properties of these agents in addition to modulation of gamma-aminobutyric acid, serotonin, and other neurotransmitters. Treatment selection is complicated by the inconsistent availability of randomized controlled data among the growing range of choices. Moreover, generalization of psychiatric to neuropsychiatric applications of anticonvulsant treatments is not universally applicable. This paper reviews the use of newer anticonvulsants in the management of neuropsychiatric disorders, particularly aggression and agitation. The largest body of treatment data is available for valproic acid, which appears to be efficacious and well-tolerated in a wide range of neuropsychiatric disorders. Less consistent data are available for other medications. Further prospective studies are warranted to examine the use of these medications in neuropsychiatric populations.

Anticonvulsants↗

PubMed2002

Absence of the CAAX endoprotease Rce1: effects on cell growth and transformation.

After isoprenylation, the Ras proteins and other CAAX proteins undergo two additional enzymatic modifications-endoproteolytic release of the last three amino acids of the protein by the protease Rce1 and methylation of the carboxyl-terminal isoprenylcysteine by the methyltransferase Icmt. This postisoprenylation processing is thought to be important for the association of Ras proteins with membranes. Blocking postisoprenylation processing, by inhibiting Rce1, has been suggested as a potential approach for retarding cell growth and blocking cellular transformation. The objective of this study was to develop a cell culture system for addressing these issues. We generated mice with a conditional Rce1 allele (Rce1(flox)) and produced Rce1(flox/flox) fibroblasts. Cre-mediated excision of Rce1 (thereby producing Rce1(Delta/Delta) fibroblasts) eliminated Ras endoproteolytic processing and methylation and caused a partial mislocalization of truncated K-Ras and H-Ras fusion proteins within cells. Rce1(Delta/Delta) fibroblasts grew more slowly than Rce1(flox/flox) fibroblasts. The excision of Rce1 also reduced Ras-induced transformation, as judged by the growth of colonies in soft agar. The excision of Rce1 from a Rce1(flox/flox) skin carcinoma cell line also significantly retarded the growth of cells, and this effect was exaggerated by cotreatment of the cells with a farnesyltransferase inhibitor. These studies support the idea that interference with postisoprenylation processing retards cell growth, limits Ras-induced transformation, and sensitizes tumor cells to a farnesyltransferase inhibitor.

Alkyl and Aryl Transferases↗